A family of phosphoinositide 3-OH kinases (PI3K) biosynthesize D-3 phosphorylated inositol lipids. See, for example, Toker, A. and Cantley, L. C. Nature 387:673-676 (1997). These enzymes phosphorylate phosphatidylinositol, phosphatidylinositol-4- phosphate and phosphatidylinositol-4,5-bisphosphate on the D-3 position of the inositol ring to generate phosphatidylinositol-3-phosphate (PI(3)P), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P.sub.2) and phosphatidylinositol-3,4,5-trisphosphate (PIP.sub.3), respectively. Some forms of PI3K, such as that of yeast Vps34p and its homologues, produce exclusively PI(3)P. In mammalian cells, PI(3)P is usually constitutively present.
PI(3,4)P.sub.2 and PIP.sub.3 are normally undetectable in unstimulated cells, but their concentrations can become transiently elevated within seconds to minutes following stimulation with various growth factors or cytokines. This behavior can be indicative of signaling roles for both PI(3,4)P.sub.2 and PIP.sub.3. Various PI3Ks can be activated through both tyrosine kinase and G-protein dependent pathways. Multiple putative downstream targets have been identified including Ca.sup.2+ -independent protein kinase C (PKC) isoforms .delta., .epsilon., .zeta., and .eta., and proteins with pleckstrin homology domains such as Akt/PKB, as well as other proteins such as synaptotagamin.